D3 receptor protein

Distinct, but weak D3 dopamine receptor binding is seen in the substantia nigra (Hall et al., 1996b). Very low densities of the D3 dopamine receptor are apparent in cerebral cortex (Hall et al., 1996b). The D3 dopamine receptor is also present in low amounts in lobule 10 in the human cerebellum (Herroelen et al., 1994 Wallace and Booze, 1995). In a comparative study using [3H]PD 128907, Levant et al. (Levant and Desouza, 1993) demonstrated the D3 dopamine receptors in the rat cerebellum, but failed to show binding in the human cerebellum. 

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Rictschel Marcella, Markus M. Nothen, Lars Lannfelt, Pierre Sokoloff, Jean-Charles Schwartz, Mario Lanczik, Jurgen Fritze, Sven Cichon, Rolf Fimmers, Judith Komer, Hans-Jurgen Moller, and Peter Propping. 1993. "A Serine to Glycine Substitution at Position 9 in the Extracellular N-Terminal Part of the Dopamine D3 Receptor Protein No Role in the Genetic Predisposition to Bipolar Affective Disorder." Psychiatry Research 46 253-59. 

O Connell, T. D., Simpson, R. U. 1996. Immunochemical identification of the 1,25-dihy-droxyvitamin D3 receptor protein in human heart. Cell Biol Int, 20 621-4. 

G Protein-Coupled Receptors (GPCRs) ttiA Adrenergic Receptor Dopamine D3 Receptor Endothelin A Receptor... 

TF transcription factor, R receptor, Fur ferric uptake regulation protein, NF-kB nuclear factor-kB, AP-1 activator protein-1, Egr-1 early growth response-1, VDR la,25-dihydroxy-vitamin D3 receptor, RXR retinoid X receptor, PPARy peroxisome proliferator-activated receptor y NFAT nuclear factor of activated T-cells, HSF heat shock factor, p53 tumor suppressor p53, HIF-1 hypoxia inducible factor-1. ... 

H)2D3 exerts its influence within target tissues through high-affinity sterol-specific intracellular receptor proteins. The D3 receptor, similar to steroid receptor systems, translocates the hormone from the cell cytoplasm to the nucleus, where biological response is initiated via transcription and translation (Fig. 66.3). 

After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac l -adrenoceptor-G protein-effector system take place that result in diminished stimulatory effects. Beta2 receptors are not down-regulated and may develop increased coupling to the IP3-DAG cascade. It has also been suggested that cardiac D3 receptors (which do not appear to be down-regulated... 

The D vitamins are a group of sterols that have a hormone-like funciion. The active molecule, 1,25-dihydroxycholecalciferol (1,25 diOH D3), binds to intracellular receptor proteins. The 1,25-diOH D3-receptor complex interacts with DNA in the nucleus of target cells in a manner simiar to that of vitamin A (see Figure 28.20), and either selectively stimulates gene expression, or specifically represses gene transcription. The most prominent actions of 1,25-diOH D3 are to regulate the plasma levels of calcium and phosphorus. 

Effect of vitamin D on the intestine 1,25-diOH D3 stimulates intestinal absorption of calcium and phosphate. 1,25-diOH D3 enters the intestinal cell and binds to a cytosolic receptor. The 1,25-diOH D3-receptor complex then moves to the nucleus where it selectively interacts with the cellular DNA. As a result, calcium uptake is enhanced by an increased synthesis of a specific calcium-binding protein. Thus, the mechanism of action of 1,25-diOH D3 is typical of steroid hormones (see p. 238). 

The Di-like receptors (Di, D5) couple predominantly to Gs and thus can stimulate adenylyl cyclase, yielding cAMP. The D2-like receptors (D2, D3, D4) couple to Gi/o proteins and may inhibit adenylyl cyclase or modulate many other different signalling molecules and pathways. D3 receptors may also couple to Gs (Obadiah et al. 1999 Ilani et al. 2002). 

D2-like receptors couple mainly to Gi/o proteins, as mentioned above. However, there is no direct evidence to support this coupling for the release-modulating autoreceptors. Moreover, the subsequent intracellular signal transduction has never been studied directly in axon terminals. Mouse AtT-20 pituitary cells, which release acetylcholine and adrenocorticotropic hormone, have been used as a model for axon terminals. When expressed in these cells, D3 receptors mediated inhibition of P/Q-type calcium channels and activation of G protein-coupled inward rectifier potassium channels (Kuzhikandathil et al. 1998 Kuzhikandathil and Oxford 1999). Both would explain the autoreceptor-mediated inhibition of dopamine exocytosis. 

Similar to the D2 and D4 receptors, the D3 receptor inhibits cAMP accumulation through coupling to G proteins. In addition, the D3 receptor inhibits Ca2+ currents and promotes mitogenesis, probably via tyrosine phosphorylation and activation of mitogen-activated protein kinases (Sokoloff and Schwartz, 2003). 

Like D2 receptors, when D3 receptors are transfected in heterologous systems, they are able to stimulate Na+/H+ exchange in the cells producing an acidification of the culture medium. This effect is due to the activation of the amiloride-sensitive Na+/H+ antiporter and is dependent on a Gi/Go protein activation and partly on the inhibition of cAMP production (Chio et al., 1994a Vanhauwe et al., 1999). However, the D3 receptor stimulation appeared to be less efficiently than that of D2 receptor on this response (Chio et al., 1994a Vanhauwe et al., 1999). 

D3 receptors have coupling mechanisms qualitatively similar to D2 receptors, although this coupling seems to be less efficient. They may have a preferential ability to inhibit ACV with which they are coexpressed in the ventral striatum, and they have the possibility to interact directly with SH3 domain containing proteins, although the physiological role of this interaction remains to be established. 

In summary, the signaling pathways stimulated by D4 receptor appear to be very similar to those found for D2 and D3 receptors. The most striking difference concerns its ability to activate Gott2 protein which could confer on the D4-receptor signal transduction some particularities that remain to be clarified. 

Newman-Tancredi A, Cussac D, Audinot V, Pasteau V, Gavaudan S, Millan MJ (1999) G protein activation by human dopamine D3 receptors in high-expressing Chinese hamster ovary cells A guanosine-5 -0-(3-[35S]thio)-triphosphate binding and antibody study. Mol Pharmacol 55 564-574. 

Cussac, D. Newman-Tancredi, A. Pasteau, V. Millan, M.J. (1999) Human dopamine D3 receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol. Pharmacol. 56, 1025-1030. 

The Di-like receptors include and Dg, while the Da-like receptors encompass Dg, Dg, and D4 (531,532). The D, receptor subtype has a short (D ) and long (D2l) protein form that results Irom alternative transcription of the D22, gene. The difference between the two receptors is a 29 amino acid peptide coded by an exon that has been spliced out of the third intracellular loop Of DgL- The D3 receptor also has several variants, and the D4 receptor has multiple variants that are characterized by a different number of repeating units also located in the third cytoplasmic loop of the receptor protein (533). 

A FIGURE 11-42 Consensus sequences of DNA response elements that bind three nuclear receptors. The response elements for the glucocorticoid receptor (GRE) and estrogen receptor (ERE) contain inverted repeats that bind these homodimeric proteins. The response elements for heterodimeric receptors contain a common direct repeat separated by three to five base pairs, for the vitamin D3 receptor (VDRE), thyroid hormone receptor (TRE), and retinoic acid receptor (RARE). The repeat sequences are indicated by red arrows. [See K. Umesono etal., 1991, Ce//65 1255, and A. M. Naaretal., 1991, Ce//65 1267]... 

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